20(bets)-[(monoalkylamino)methyl]pregn-5-en-3beta-ols, esters corresponding and intermediates thereto



rates The present invention is concerned with novel steroidal amines ofthe pregnane series and, more particularly, with 20(5)[(monoalkylarnino)methyl]pregn-S-en-Bfi-ols and esters thereof, whichare represented by the structural formula OHZNH (lower alkyl) CH3C H CH3H wherein the OX radical can be hydroxy or (lower alkanoyl) -oxy.

A further object of this invention is the provision of novel 20 (,8) [N-(lower alkyl) carboxamido1-pregn-5-en- Bfl-ol- 3-acetates of thestructural formula If $-NH (lower alkyl) 0 H3 0 -11 i CHaCO ice Theaforementioned 20(5) (N isobutylcarboxamido)- pregn-5-en-3fi-ol3-acetate, for example, is treated with lithium aluminum hydride inrefluxing dioxane to yield 20 n) isobutylamino methyl] pregn-5-en-35-01.

The instant amines which contain an esterified hydroxy group at position3 can be prepared from the corresponding alcohols by reaction with theappropriate lower alkanoic acid in the'presence of an esterificationcatalyst. As a specific example, 20(5)-[(isobutylarnino)methyl]-pregn-5-en-3B-ol hydrochloride is converted to the corresponding3-acetate by reaction with acetic acid in the presence of hydrogenchloride.

Equivalent to the organic bases of this invention are the correspondingnon-toxic acid and quaternary salts, which are exemplified by thecitrate, tartrate, maleate, ascorbate, gluconate, lactate, succinate,phosphate,, sulfate, hydrobromide, hydrochloride, methobromide,methoc-hloride, methosulfate, and ethosulfate.

The compounds of the present invention exhibit valuable pharmacologicalproperties. They are, for example, potent hypocholesterolemic agents andare also inhibitors of gastrointestinal acid secretion. In addition,they lack the sodium-excreting side effect of related prior artcompositions.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade (C.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

Example 1 To a suspension of 30 parts of 20(fi)-carboxypregn-5-en-3,B-ol S-acetate in 213 parts of ether is added, with stirring, 32.8parts of thionyl chloride and 0.0 5 part of pyridine. Stirring iscontinued at room temperature for about 3 hours, during which time thereaction mixture becomes homogeneous. The volatile materials are removedby distillation at reduced pressure, and the residue is extracted withbenzene. Concentration of the benzene which are useful as intermediatesin the manufacture of Solution to dryness at reduced Pressure affordscrystals the aforementioned 20(5)-aminornethyl-3B-hydroxy compounds.

Examples of the lower alkyl radicals encompassed in the structuralformulae supra are methyl, ethyl, propyl, butyl, pentyl, hexyl, and thebranched-chain isomers thereof. Lower alkanoyl radicals represented by Xin those formulae are, typically, formyl, acetyl, propionyl, butyryl,valeryl, caproyl, and their branched-chain isomers.

The compounds of this invention can be manufactured by starting with20(5)-carboxypregn-5-en-3fl-o1 3-acetate. This carboxylic acid isconverted to the corresponding acid chloride, suitably by reaction withthionyl chloride in the presence of a catalytic quantity of pyridine.That acid chloride is allowed to react with the appropriate aliphaticprimary amine in a suitable inert organic solvent to yield thecorresponding intermediate 20(fi)-[N-(lower a1kyl)-carboxamido]pregn-5-en-35-ol 3-acetate. This process is typified by thereaction of 20(3)-chlorocarbonylpregn-5- en-3B-0l 3-acetate withisobutylamine in benzene to produce 20(5)(N-isobutylcarboxamido)pregn-5-en-3fi-ol 3- acetate. Reduction of theseintermediate amides, suitably by means of lithium aluminum hydride,affords the instant 20 (,8) (monoalkylamino) methyl] pregn-5-en-3 p-ols.

of 20(5)-chlorocarbonylpregn-5-en-3,8-ol 3-acetate, which is representedby the following structural formula II OHaCO Example 2 Example 3 I]CHsOO To a refluxing suspension of 10 parts of lithium aluminum hydridein 206 parts of dioxane is added dropwise, with stirring, a solution of10 parts of 20(B)-(N- isopropylcarboxamido)pregrl-S-en-Ilfl-ol 3-acetatein 103 parts of dioxane. Refluxing is continued for about 16 hours, atthe end of which time the reaction mixture is cooled and cautious-1ytreated by the successive addition of 10 parts of water, 8 parts of 20%aqueous sodium hydroxide, and 35 parts of water. The precipitated saltsare removed by filtration and washed on the filter with dioxane. Thefiltrate is diluted with ethyl acetate and ether, then washed withwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to a crystalline solid, which is20({3)-[(isopropylamino)- methylJpregn-S-en-318-o1.

A solution of the latter amine in methanol is acidified withisopropanolic hydrogen chloride, and is diluted with about volumes ofether. The resulting precipitate is Washed on the filter with ether, isdried, then is recrystallized from methanol-ethyl acetate to yield pure20(5)- [(isopropylamino)methylJpregn 5 en-3fl-ol hydrochloride of thestructural formula (lHzNHC .HCl CH C-H CH CH3 nae/lW l Example 4 4Example 5 A solution of 5 parts of20(5)-(N-isobutyl-carboxamido)pregn-5-en-3B-ol 3-acetate in 50 parts ofdioxane is added dropwise to a refluxing slurry of 5 parts of lithiumaluminum hydride in 103 parts of dioxane. The reaction mixture is heatedat the reflux temperature for about 16 hours, then is cooled. To thecooled solution is added successively 5 parts of water, 4 parts of 20%aqueous sodium hydroxide, and 18 parts of water. The resultingprecipitate is removed by filtration and washed on the filter withdioxane. Dilution of the filtrate with ether and ethyl acetate affordsan organic solution, which is washed with water, dried over anhydroussodium sulfate, and concentrated to dryness in vacuo to yield 20(3)-isobutylamino methyl] pregn-S -en-3 [3-01.

Dissolution of the latter amine in methanol followed by acidificationwith isopropanolic hydrogen chloride and dilution with ether affords thecrude hydrochloride, which is collected by fitration, washed with ether,dried and recrystallized from methanolethyl acetate to afford pure20(5)-[isobutylamino)methyl]-preg'n 5 en-Sfi-ol hydrochloride, MiP.about 280300 (dec.). It has the structural formula CH CH2NHOH2C .HCI

CH3CH CH3 CH3 H3O Example 6 The substitution of 25.6 parts ofisoamylamine for isopropylamine in the procedure described in Example 2results in 20(5) (N-isoamylcarboxamido)pregn-5-en-3flol 3-acetate. Itsis represented by the structural formula By substituting 10 parts of20(B)-(N-isoamylcarboxarnido)pregn-5-en-3B-ol 3-acetate and otherwiseproceeding according to the processes of Example 3,20({3)-[(isoamylamino)methyl]pregn-5-en-3,B-ol hydrochloride is ob- Asolution of 10 parts of 20(B)-[(isobutylamino)- CH C HzNH C Hz C Ha-C HC H 011 H30 1? C Ha C 0 Example 9 The reaction of 5 parts of20(fi)-[(isoproplyarnino)- methylJpregn-S-en-3fi-ol hydrochloride and 50parts of propionic acid, containing 3% by weight of anhydrous hydrogenchloride, according to the process of Example 8 results in20(fi)-[(isopropylarnino)methyl]pregn-5'-en- 35-01 3-propionate of thestructural formula /OH OHzNHC CHa-O-H it CHsCHnOO 6 What is claimedis: 1. A compound of the structural formula CH2NH (lower alkyl) whereinX is selected from the group consisting of hydrogen and lower alkanoylradicals.

2. 20(fi)-[(isopropylamino)methyl]pregn-S-efl-SB-ol. 3. 20(5)(isobutylamino)rnethyl] pregn-5-en-3 3-0l. 4. 20(13)-[(isoamylamino)methyl]pregn-S-en-BB-ol. 5.A compound of the structuralformula -NHOower alkyl) CH -C-H CH3 H30 I3 ll CHsCO 6. 20(B)-(Nisopropylcarboxarnido)pregn-S-en-Bfi-ol 3-acetate. 7.20(5)-(N-isobutylcanhoxamido)pregn-S-en 33-01 3- acetate.

8. 20(13)-(N-isoamylcarboxamido)pregn-S-en- 35-01 3- acetate.

References Cited in the file of this patent UNITED STATES PATENTSBockmuhl et a1. Feb. 15. 1938

5. A COMPOUND OF THE STRUCTURAL FORMULA